Metallic silver, silver salts (e.g., AgNO3), and silver complexes have been employed most extensively since ancient times to fight infections and control spoilage in a variety of pharmaceutical and health care applications including anti-infective coatings in medical devices, post-operative wound management and burn wound treatment. Because the metal attacks a broad range of targets in the organisms, microbes are unlikely to develop a resistance against silver, as they do against conventional and highly targeted antibiotics. Indeed, they would have to develop a host of mutations simultaneously to protect themselves. It has been noted that silver ions are responsible for the antibacterial activity. The antibacterial mechanisms of silver may include modifications of sulfur-containing membranes, inhibition of the function of respiratory enzyme(s) facilitating the generation of reactive oxygen species, and inactivation of expression of ribosomal subunit proteins as well as some other cytoplasmic proteins and enzymes essential to ATP production.
Burn wounds, especially large burn wounds, are a critical threat to burn victims, causing dehydration, systemic infection, and other complications. The use of antibacterial agents locally or systemically inhibits microorganism growth around the wound, allowing a suitable microenvironment for healing. The application of silver and its salts in the treatment of burn wounds is thus of special interest, and has prompted an upsurge in research on the synthesis of silver (I) complexes with projected antibacterial application.
There are a variety of inorganic silver-containing antibacterial agents available in practices. For example, U.S. Pat. Nos. 4,911,898 and 4,938,958 disclosed the techniques for carrying sliver zeolite. U.S. Pat. Nos. 5,296,238 and 5,441,717 disclosed the techniques of silver-containing inorganic zirconium phosphate antibacterial agents, such as Ag0.16Na0.84Zr2(PO4)3, Ag0.05H0.05Na0.90Zr2(PO4)2 and etc.
Japanese patents 6-263612 and 6-263613 disclosed silver-containing antibacterial agents, such as silver-containing zirconium phosphate, (and silver-containing stannum, phosphate, and silver-containing titanium phosphate), dissolved within the organic solvent to be ground by zirconia spheres under a dispersant agent so as to increase its antibacterial activity. JP2000-68914 disclosed the use of applying acetic acid into inorganic antibacterial agents to increase its antibacterial performance. These antibacterial agents described above are essentially monovalent silver antibacterial agents.
However, such antibacterial agents containing monovalent silver known in prior art are not pharmaceutically acceptable especially for burn and wound care treatment. N-heterocyclic carbene silver (I) complexes have good antibacterial property, but decompose in aqueous solutions. Therefore, for better exploitation of silver-based antibacterial therapies in medicine it is necessary to develop new pharmaceutically acceptable and stable silver complexes.
Even though antibacterial agents containing monovalent silver demonstrate good antibacterial efficacy, monovalent silver is very photosensitive. Upon exposure to electromagnetic radiation it undergoes discoloration. The antibacterial performance of silver ion is correlated to its valence form and although antibacterial performance of the different silver valence varies in treating heterogeneous bacteria, it is generally known that high valence silver ions exhibit stronger and more effective antibacterial action than low valence ions.
It is widely known that divalent silver has higher antibacterial performance than monovalent silver. US Pat. Appl. No. 20070042052 disclosed antibacterial agents containing divalent silver. However, such divalent sliver will be only kept stable in concentrated acidic environment. As a result, it would be rather difficult and dangerous for the operation, usage, and transportation of such agents. U.S. Pat. No. 5,089,275 disclosed a type of solid antibacterial compound containing divalent silver. This compound is prepared by reacting an acidic fluid divalent silver complex with anhydrous calcium sulfate so as to obtain a stable hydrated solid.
Although the solid antibacterial agents containing divalent silver solves the issue of the liquid state of divalent silver antibacterial agents, the product still faces the deficiency of long term storage stability in solid state. Therefore, the field of application is limited due to the fact to its water solubility. i.e. such solid antibacterial agents have to be used in cleaning water, such as swimming pool, bathtub, industry cooling system, and so on.
Encouraging results have recently been reported regarding the bactericidal activity of silver nanoparticles of either simple or composite nature. The high surface to volume ratio of nanoparticles ensures that a significantly large surface area of the particle is in contact with the bacteria. Smaller particle size silver sulfadiazine product demonstrates increased antibacterial effectiveness and these smaller particles are better stabilized by adsorbed surfactant.
Encouraged by this finding and by the pressing interest in developing silver-containing antibacterial agents with excellent optical stability and antibacterial activity, the present inventors have found that a silver/polydiguanide complex of the present invention is different from conventional silver/polydiguanide complexes in carbon, hydrogen, and nitrogen contents as well as in structure of silver and polydiguanide, and solubility, is a material that exhibits a very good antibacterial activity due to a much lower minimal inhibitory concentration (MIC) value by 10 to 100 folds or more compared to silver sulfadiazine which is a conventional therapeutic agent for burns, and may be usefully used as an antibacterial composition for burns or wounds treatment, leading to completion of the present invention.